Radical Approach to Enzymatic β-Thioether Bond Formation.

TitleRadical Approach to Enzymatic β-Thioether Bond Formation.
Publication TypeJournal Article
Year of Publication2019
AuthorsCaruso, A, Bushin, LB, Clark, KA, Martinie, RJ, Seyedsayamdost, MR
JournalJ Am Chem Soc
Volume141
Issue2
Pagination990-997
Date Published2019 01 16
ISSN1520-5126
KeywordsAmino Acid Sequence, Bacterial Proteins, Carbon-Sulfur Lyases, Models, Chemical, Multigene Family, Peptide Biosynthesis, Peptides, Protein Processing, Post-Translational, S-Adenosylmethionine, Streptococcus, Sulfides
Abstract

<p>Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an emerging class of natural products that harbor diverse chemical functionalities, usually introduced via the action of a small number of tailoring enzymes. We have been interested in RiPP biosynthetic gene clusters that encode unusual metalloenzymes, as these may install as yet unknown alterations. Using a new bioinformatic search strategy, we recently identified an array of unexplored RiPP gene clusters that are quorum sensing-regulated and contain one or more uncharacterized radical S-adenosylmethionine (RaS) metalloenzymes. Herein, we investigate the reaction of one of these RaS enzymes and find that it installs an intramolecular β-thioether bond onto its substrate peptide by connecting a Cys-thiol group to the β-carbon of an upstream Asn residue. The enzyme responsible, NxxcB, accepts several amino acids in place of Asn and introduces unnatural β-thioether linkages at unactivated positions. This new transformation adds to the growing list of Nature's peptide macrocyclization strategies and expands the already impressive catalytic repertoire of the RaS enzyme superfamily.</p>

DOI10.1021/jacs.8b11060
Alternate JournalJ Am Chem Soc
PubMed ID30521328